Multiple autoimmune disease is characterized by the co-occurrence of two or more of various autoimmune disorders in individuals, and often also in their family members. Perhaps the most common form of multiple autoimmune disease is so-called 'autoimmune polyendocrine syndrome type 2' (APS2), classically characterized by the co-occurrence of Addison's disease, autoimmune thyroid disease (Graves' disease and hypothyroidism), type 1 diabetes mellitus, celiac disease, hypogonadism, vitiligo, alopecia, pernicious anemia, and myasthenia gravis, but occasionally systemic lupus erythematosus, juvenile rheumatoid arthritis, multiple sclerosis, and other disorders. APS2 appears to represent a constellation of disorders controlled by multiple genes that predispose to autoimmunity, most likely acting at several different biological levels, in concert with environmental factors. We have defined a sub-group of multiple autoimmune disease, which we term 'multiple autoimmunity syndrome', which includes a specific constellation of associated disorders; vitiligo, autoimmune thyroid disease, pernicious anemia, Addison's disease, lupus and perhaps inflammatory bowel disease. We have ascertained a large number of multiple autoimmunity syndrome families in which different individuals have different combinations of these specific diagnoses. In these families, susceptibility to this specific constellation of autoimmune diseases appears to be inherited as an autosomal dominant trait with reduced penetrance. We plan to collect samples from these families and carry out genome-wide genotyping and genetic linkage analyses for the purpose of mapping the genetic loci that predispose to this form of multiple autoimmune disease. We will then carry out more detailed mapping to define the genetic intervals, and subsequently screen positional candidate genes for pathologic mutations. The effects of these mutations will be tested in functional analyses that will provide ultimate confirmation of gene identification. The genes that predispose to this constellation of associated diseases will likely be different from those associated with susceptibility to the individual components of this group of diseases. We anticipate that these studies will shed light on the mechanisms of autoimmunity itself, as well as the autoimmune mechanisms that underlie these individual autoimmune diseases.